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A population based cohort study of patients with multiple colon and endometrial cancer: correlation of microsatellite instability (MSI) staus, age at diagnosis and cancer risk
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
Vise andre og tillknytning
2001 (engelsk)Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 91, nr 4, s. 486-491Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Hereditary non-polyposis colorectal cancer, HNPCC, is an autosomal dominant condition predisposing to cancers of primarily the colorectum and the endometrium. The aim of our study was to identify persons at a high risk of hereditary colorectal cancer and to estimate their risk of colon and other HNPCC-associated tumours. Family histories of cancer were obtained on 89 persons with double primary (DP) cancers of the colon and the endometrium. The cancer risks in their 649 first-degree-relatives (FDR) were analysed. The microsatellite instability (MSI) status of the tumour of the proband was also analysed and the cancer risks were estimated in relation to MSI status and age at diagnosis in the proband (over or under 50 years). The overall standardised incidence ratio (SIR) was 1.69 (95% CI; 1.39-2.03). In the =50-year-old cohort the SIR was 2.67 (95% CI; 2.08-3.38). Colon, rectal and uterus cancer exhibited significantly increased risks. This risk was further increased in the =50-year-old MSI positive families. Several =50-year-old MSI negative HNPCC-like families with increased risks were also identified. In conclusion a FDR to a person with a DP cancer of the colorectum or the colon/endometrium have a significantly increased risk of having a colorectal or other HNPCC-associated cancers if the proband is diagnosed with one of the cancers before age 50. These families are candidates for genetic counselling and colorectal screening programmes. Mutations in mismatch repair genes can explain some of the increased risk in these families, but mutations in MSI negative families are probably due to other colon cancer susceptibility genes not yet described. Copyright 2001 Wiley-Liss, Inc.

sted, utgiver, år, opplag, sider
2001. Vol. 91, nr 4, s. 486-491
Emneord [en]
HNPCC; MSI; double primary tumour; mismatch repair genes; cancer risk
Identifikatorer
URN: urn:nbn:se:umu:diva-4760DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1093>3.0.CO;2-PPubMedID: 11251970OAI: oai:DiVA.org:umu-4760DiVA, id: diva2:143991
Tilgjengelig fra: 2005-10-19 Laget: 2005-10-19 Sist oppdatert: 2017-12-14bibliografisk kontrollert
Inngår i avhandling
1. Genetic and epidemiological studies of hereditary colorectal cancer
Åpne denne publikasjonen i ny fane eller vindu >>Genetic and epidemiological studies of hereditary colorectal cancer
2005 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is the most common hereditary syndrome predisposing to colorectal cancer, accounting for 1-3% of all colorectal cancer. This multi-organ cancer predisposition syndrome is caused by mutations in the mismatch repair (MMR) genes, especially MLH1 and MSH2, and to lesser extents MSH6 and PMS2, which lead to widespread genetic instability and thus microsatellite instability (MSI). Hereditary cancer often manifests in two or more tumours in a single individual; 35-40% of Lynch syndrome patients have synchronous or metachronous tumours of the two major Lynch syndrome-related cancers: colorectal and endometrial.

The main purposes of the work underlying this thesis were to identify persons at risk of Lynch syndrome or other types of hereditary colorectal cancer, to estimate the cancer risks associated with these predispositions and to identify the underlying genetic causes.

A population-based cohort of 78 persons with double primary colorectal or colorectal and endometrial cancer was identified. Cancer risks in their 649 first-degree relatives were estimated in relation to tumour MSI status (positive or negative) and age at diagnosis (before or after 50 years of age) in the probands. The overall standardised incidence ratio was 1.69 (95% CI; 1.39-2.03). The highest risks for Lynch syndrome-associated cancers: (colorectal, endometrial, ovarian and gastric) were found in families with young MSI-positive probands, likely representing Lynch syndrome families. Importantly, no overall risk was found in families with old probands, irrespective of MSI status.

Blood samples were available from 24 MSI-positive patients for mutation screening of MLH1, MSH2 and MSH6. Sequence variants or rearrangements predicted to affect protein function were found in 16 patients. Six novel variants were found: two large rearrangements, two truncating and two missense mutations. The missense mutations were found to segregate in the families. Studies of allele frequencies, MSI and loss of immunostaning in tumours from family members further supports the hypothesis that these missense changes play a role in Lynch syndrome, as do the non-conservative nature and evolutionary conservation of the amino acid exchanges. Five families had mutations in MLH1, five in MSH2, and six in MSH6. The unexpectedly large impact of MSH6 was in genealogical studies shown to be due to a founder effect. Cumulative risk studies showed that the MSH6 families, despite their late age of onset, have a high lifetime risk for all Lynch syndrome-related cancers, significantly higher in women (89% by age 80 years) than in men (69%). The gender differences are in part due to high endometrial (70%) and ovarian cancer risk (33%) in addition to the high colorectal cancer risk (60%). These findings are of great importance for counselling and surveillance of families with MSH6 mutations.

Finally, in a large family with MSI-negative hereditary colorectal cancer for which the MMR genes and APC had been excluded as possible causes, a genome-wide linkage analysis was performed, resulting in a suggested linkage to chromosome 7.

Conclusions: Relatives of probands with MSI-positive, double primary colorectal and endometrial cancer diagnosed before the age of 50 years have significantly increased risks of Lynch syndrome-related cancers. MSH6 mutations, which have unusually high impact in this study population due to a founder effect, confer high cumulative risks of cancer despite the generally late age of onset.

Publisher
s. 86
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 980
Emneord
Genetics, Lynch syndrome, HNPCC, colorectal cancer, endometrial cancer, cancer risk, MSI, MLH1, MSH2, MSH6, genome-wide scan, Genetik
HSV kategori
Forskningsprogram
medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-615 (URN)91-7305-937-4 (ISBN)
Disputas
2005-11-18, Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2005-10-19 Laget: 2005-10-19 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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